Multiple Reaction Monitoring Mass Spectrometry for the Drug Monitoring of Ivacaftor, Tezacaftor, and Elexacaftor Treatment Response in Cystic Fibrosis: A High-Throughput Method

Reyes-Ortega, Felisa; Qiu, Fiona; Schneider‐Futschik, Elena K.

doi:10.1021/acsptsci.0c00103

Cited by 25 publications

(12 citation statements)

References 21 publications

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“…Ivacaftor, Elexacaftor, and Tezacaftor were all identified in the sputum metabolome by MS/MS analysis with similar fragmentation behavior to that described by Reyes-Ortega et al (2020) [30] . This included the known and unknown metabolized products of the parent drugs with related MS/MS spectra ( Fig.…”

Section: Eti Metabolism In Cf Mucussupporting

confidence: 74%

A restructuring of microbiome niche space is associated with Elexacaftor-Tezacaftor-Ivacaftor therapy in the cystic fibrosis lung

Sosinski¹,

H²,

Neugebauer³

et al. 2022

Journal of Cystic Fibrosis

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Section: Eti Metabolism In Cf Mucussupporting

confidence: 74%

A restructuring of microbiome niche space is associated with Elexacaftor-Tezacaftor-Ivacaftor therapy in the cystic fibrosis lung

Sosinski¹,

H²,

Neugebauer³

et al. 2022

Journal of Cystic Fibrosis

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“…ETI is a triple therapy of the compounds Ivacaftor, Elexacaftor, and Tezacaftor. All three drugs were identified in the sputum metabolome by MS/MS analysis with similar fragmentation behavior to that described by Reyes-Ortega et al (2020) (30). This included the known and unknown metabolized products of the parent drugs with related MS/MS spectra (Fig.…”

Section: Resultssupporting

confidence: 72%

Trikafta therapy alters the CF lung mucus metabolome reshaping microbiome niche space

Sosinski

Martin-Hernandez

et al. 2021

Preprint

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Novel small molecule therapies for cystic fibrosis (CF) are showing promising efficacy and becoming more widely available since recent FDA approval. The newest of these is a triple therapy of Elexacaftor-Tezacaftor-Ivacaftor (ETI). Little is known about how these drugs will affect polymicrobial lung infections, which are the leading cause of morbidity and mortality among people with CF (pwCF). We analyzed the sputum microbiome and metabolome from pwCF (n=24) before and after TKT therapy using 16S rRNA gene amplicon sequencing and untargeted metabolomics. The lung microbiome diversity, particularly its evenness, was increased (p = 0.044) and the microbiome profiles were different between individuals before and after therapy (PERMANOVA F=1.92, p=0.044). Despite these changes, the microbiomes were more similar within an individual than across the sampled population. There were no specific microbial taxa that were different in abundance before and after therapy, but collectively, the log-ratio of anaerobes to pathogens significantly decreased. The sputum metabolome also showed changes due to TKT. Beta-diversity increased after therapy (PERMANOVA F=4.22, p=0.022) and was characterized by greater variation across subjects while on treatment. This significant difference in the metabolome was driven by a decrease in peptides, amino acids, and metabolites from the kynurenine pathway. Metabolism of the three small molecules that make up TKT was extensive, including previously uncharacterized structural modifications. This study shows that TKT therapy affects both the microbiome and metabolome of airway mucus. This effect was stronger on sputum biochemistry, which may reflect changing niche spaces for microbial residency in lung mucus as the drug effects take hold, which then leads to changing microbiology.

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“…Details of methods for LC–MS analysis have been previously described. − Serum, lung, and BALF samples were analyzed with a Shimadzu 8050 LC–MS system coupled with 8050 triple quadrupole mass spectrometers.…”

Section: Methodsmentioning

confidence: 99%

Ivacaftor Alters Macrophage and Lymphocyte Infiltration in the Lungs Following Lipopolysaccharide Exposure

Harwood

McQuade

Jarnicki

et al. 2022

ACS Pharmacol. Transl. Sci.

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Background and purpose: Cystic fibrosis (CF) is associated with a myriad of respiratory complications including increased susceptibility to lung infections and inflammation. Progressive inflammatory insults lead to airway damage and remodeling, resulting in compromised lung function. Treatment with ivacaftor significantly improves respiratory function and reduces the incidence of pulmonary exacerbations; however, its effect on lung inflammation is yet to be fully elucidated. Experimental approach: This study investigates the effects of ivacaftor on lung inflammation in a lipopolysaccharide (LPS) exposure mouse model (C57BL/6). All groups received intratracheal (IT) administration of LPS (10 μg). Prophylactic treatment involved intraperitoneal injections of ivacaftor (40 mg/kg) once a day beginning 4 days prior to LPS challenge. The therapeutic group received a single intraperitoneal ivacaftor injection (40 mg/kg) directly after LPS. Mice were culled either 24 or 72 h after LPS challenge, and serum, bronchoalveolar lavage fluid (BALF), and lung tissue samples were collected. The degree of inflammation was assessed through cell infiltration, cytokine expression, and histological analysis. Key results: Ivacaftor did not decrease the total number of immune cells within the BALF; however, prophylactic treatment did significantly reduce macrophage and lymphocyte infiltration. Prophylactic treatment exhibited a significant negative correlation between the immune cell number and ivacaftor concentrations in BALF; however, no significant changes in the cytokine expression or histological parameters were determined. Conclusions and implications: Ivacaftor possesses some inherent immunomodulatory effects within the lungs following LPS inoculation; however, further analysis of larger sample sizes is required to confirm the results.

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Multiple Reaction Monitoring Mass Spectrometry for the Drug Monitoring of Ivacaftor, Tezacaftor, and Elexacaftor Treatment Response in Cystic Fibrosis: A High-Throughput Method

Cited by 25 publications

References 21 publications

A restructuring of microbiome niche space is associated with Elexacaftor-Tezacaftor-Ivacaftor therapy in the cystic fibrosis lung

A restructuring of microbiome niche space is associated with Elexacaftor-Tezacaftor-Ivacaftor therapy in the cystic fibrosis lung

Trikafta therapy alters the CF lung mucus metabolome reshaping microbiome niche space

Ivacaftor Alters Macrophage and Lymphocyte Infiltration in the Lungs Following Lipopolysaccharide Exposure

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